Risk of carcinoma, pre-malignancies persisted for up to 20 years, experts found

Action Points

Note that this observational study found that women with a previous diagnosis of CIN3 had a dramatically increased risk of HPV-associated malignancies even decades after the initial diagnosis.

It remains unclear how effective vaccinating all women with CIN3 against HPV would be to stem the risk of malignancy.

The increased risk for HPV-related carcinomas and pre-malignancies of the anogenital and oropharyngeal region can last for decades after a diagnosis of cervical intra-epithelial neoplasia grade 3 (CIN3), leaving previously diagnosed older and unvaccinated women at significant risk, according to researchers.

A population-based cohort study of women with an earlier diagnosis of CIN3 and matched controls revealed incidence rate ratios (IRRs) of 86.08 for vaginal cancer, 25.65 for vaginal intraepithelial neoplasia grade 3 (VAIN3), 4.97 for vulvar cancer, and 13.66 for vulvar intraepithelial neoplasia grade 3 (VIN3), according to Renee Ebisch, MD, of Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues.

The study, which was published in the Journal of Clinical Oncology, also revealed IRRs of 5.51 for oropharyngeal cancer, 3.85 for anal cancer, and 6.68 for anal intraepithelial neoplasia grade 3 (AIN3).

"The increased risk was still present up to 20 years after the CIN3 diagnosis," the researchers said. This provides "further evidence of the increased risk of HPV-related carcinomas and pre-malignancies of the anogenital and oropharyngeal regions after a diagnosis of CIN3, and gives a clear view of women at risk for HPV-related disease," they noted, adding that "studies that investigate methods to prevent this increased risk in this group of patients, such as intensified screening or vaccination, are warranted."

These findings are in keeping with previous studies, the study authors said, noting that no studies have analyzed the risk of HPV-related high-grade pre-malignancies. "Because vaccination programs for young women only started in 2007, it will take many more years before the effects of HPV vaccination become visible in the total adult female population," they wrote.

In cervical cancer, the prevalence of a high-risk human papillomavirus (hrHPV) is almost 100%, the researchers noted. In vaginal cancers, the prevalence of hrHPV is 60% to 70%, and ranges from 20% to 50% in vulvar cancer. High-risk HPV is also found in up to 65% of oropharyngeal cancers and in 88% to 95% of anal cancers.

"Knowledge of this risk is important to preventing the development and progression of other HPV-related pre-malignancies and carcinomas, by considering prophylactic HPV vaccination and/or by paying increased attention to other HPV-related carcinomas and pre-malignancies when CIN3 identified," the study authors said. Surveillance studies of the impact of prophylactic HPV vaccination in countries with a female vaccination coverage of 50% or more show that a 68% reduction in type 16 and 18 infections, they noted.

"These HPV-related cancers and pre-malignancies are completely preventable by HPV vaccination, Stephanie Blank, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who wasn't involved in the study, said in an email.

"I would say this study is a call to action to increase HPV vaccination among girls and boys," she told MedPage Today, emphasizing that "HPV vaccination for boys and girls will reduce the long-lasting risk of HPV-related cancers and pre-cancers for both women and men."

For the study, the Dutch nationwide registry (PALGA) was used to identify 89,018 women with a previous diagnosis of CIN3 between 1990 and 2010, and the same number of matched controls. The median age at diagnosis was 35 years in women with a previous diagnosis of CIN3, and 36 years in the control group.

In those with a previous CIN3 diagnosis, 299 HPV-related carcinomas and 634 HPV-related pre-malignancies were diagnosed compared to 48 HPV-related carcinomas and 50 HPV-related pre-malignancies. The median follow-up was 14 years.

Almost all IRRs showed a steady decline of increased risk during the long-term follow-up, with the lowest increased risk after 20 to 24 years. Decreasing IRRs with advancing age was also observed in clusters of all carcinomas and/or all pre-malignancies. However, the low incidence of malignancies in younger age groups could be a confounding factor, the researchers warned, adding that the data "should be interpreted with some caution."

The role of prophylactic HPV vaccination in adult women remains controversial, the study authors noted, adding that it is still not clear "how clinically and cost effective prophylactic hrHPV vaccination would be in women treated for CIN3." They added that randomized controlled trials and cost-effectiveness studies "might answer these questions."

Nevertheless, patients should still be told about the increased risk, Ebisch and colleagues emphasized. In Holland, for example, guidelines now advise that hrHPV vaccination be considered in women with CIN3, "until more conclusive evidence on vaccine effect after treatment of CIN3 is available."

These findings underscore the importance of continued surveillance in women with a previous diagnosis of CIN3, said Hye Sook Chon, MD, of Moffitt Cancer Center in Tampa. However, more data on the effect of vaccination in this group of patients is needed before any changes to current guidelines or clinical management can be made, she told MedPage Today.

"At this time, we need to focus on counseling women with CIN3 for their risk of carcinomas and pre-malignancies of the anus, vulva, and vagina under current guidelines," Chon said. In the meantime, clinicians should stay on high alert for HPV-related lesions during follow-up colposcopy in these patients and an examination of the vaginal walls should be included as per current guidelines, the study authors suggested. Screening for vulvar and anal carcinoma and pre-malignancies can also be easily combined with cervical diagnostics, they said.

In the event of an abnormal cervical smear, vaginoscopy should be considered and VAIN treated with surgical excision, laser evaporation, or imiquimod. There are also no screening programs for VIN or AIN, or oropharyngeal lesions, the study authors noted.

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